Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Activation of the JAK/STAT pathway in Behcet’s disease

Genes & Immunity volume 16, pages 170–175 (2015)Cite this article

Subjects

An Erratum to this article was published on 05 March 2015

This article has been updated

Abstract

Th1/Th17-type T-cell responses are upregulated in Behcet’s disease (BD). However, signaling pathways associated with this aberrant immune response are not clarified. Whole-genome microarray profiling was performed with human U133 (Plus 2.0) chips using messenger RNA of isolated CD14+ monocytes and CD4+ T cells from peripheral blood mononucleated cell (PBMC) in patients with BD (n=9) and healthy controls (HCs) (n=9). Flow cytometric analysis of unstimulated (US) and stimulated (phytohaemagglutinin) signal transducer and activator of transcription (STAT3) and pSTAT3 expressions of PBMCs were also analyzed (BD and HC, both n=26). Janus family of kinase (JAK1) was observed to be upregulated in both CD14+ monocytes (1.95-fold) and CD4+ T lymphocytes (1.40-fold) of BD patients. Using canonical pathway enrichment analysis, JAK/STAT signaling was identified as activated in both CD14+ monocytes (P=9.55E−03) and in CD4+ lymphocytes (P=8.13E−04) in BD. Interferon signaling was also prominent among upregulated genes in CD14+ monocytes (P=5.62E−05). Glucocorticoid receptor signaling and interleukin (IL-6) signaling were among the most enriched pathways in differentially expressed genes in CD14+ monocytes (P=2.45E−09 and 1.00E−06, respectively). Basal US total STAT3 expression was significantly higher in BD (1.2 vs 3.45, P<0.05). The JAK1/STAT3 signaling pathway is activated in BD, possibly through the activation of Th1/Th17-type cytokines such as IL-2, interferon (IFN-γ), IL-6, IL-17 and IL-23.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

Change history

  • 05 March 2015

    This article has been corrected since Advance Online Publication and an erratum is also printed in this issue.

References

  1. Direskeneli H . Autoimmunity vs autoinflammation in Behcet's disease: do we oversimplify a complex disorder? Rheumatology (Oxford) 2006; 45: 1461–1465.

    Article  CAS  Google Scholar 

  2. Hughes T, Coit P, Adler A, Yilmaz V, Aksu K, Düzgün N et al. Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease. Nat Genet 2013; 45: 319–324.

    Article  CAS  Google Scholar 

  3. Frassanito M, Dammacco R, Cafforio P, Dammacco F . Th1 polarization of the immune response in Behcet's disease. Arthritis Rheum 1999; 42: 1967–1974.

    Article  CAS  Google Scholar 

  4. Imamura Y, Kurokawa MS, Yoshikawa H, Nara K, Takada E, Masuda C et al. Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease. Clin Exp Immunol 2005; 139: 371–378.

    Article  CAS  Google Scholar 

  5. Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S et al. Type 17 T helper cells-origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009; 5: 325–331.

    Article  CAS  Google Scholar 

  6. Hreggvidsdottir HS, Noordenbos T, Baeten DL . Inflammatory pathways in spondyloarthritis. Mol Immunol 2014; 57: 28–37.

    Article  CAS  Google Scholar 

  7. Remmers EF, Cosan F, Kirino Y, Ombrello MJ, Abaci N, Satorius C et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease. Nat Genet 2010; 42: 698–702.

    Article  CAS  Google Scholar 

  8. Hamzaoui K . Th17 cells in Behcet's disease: a new immunoregulatory axis. Clin Exp Rheumatol 2011; 29: S71–S76.

    PubMed  Google Scholar 

  9. Direskeneli H, Fujita H, Akdis CA . Regulation of TH17 and regulatory T cells in patients with Behcet disease. J Allergy Clin Immunol 2011; 128: 665–666.

    Article  CAS  Google Scholar 

  10. Chi W, Zhu X, Yang P, Liu X, Lin X, Zhou H et al. Upregulated IL-23 and IL-17 in Behcet patients with active uveitis. Invest Ophthalmol Vis Sci 2008; 49: 3058–3064.

    Article  Google Scholar 

  11. Geri G, Terrier B, Rosenzwajg M, Wechsler B, Touzot M, Seilhean D et al. Critical role of IL-21 in modulating TH17 and regulatory T cells in Behcet disease. J Allergy Clin Immunol 2011; 128: 655–664.

    Article  CAS  Google Scholar 

  12. Hamzaoui K, Bouali E, Ghorbel I, Khanfir M, Houman H, Hamzaoui A et al. Expression of Th-17 and RORgammat mRNA in Behcet's Disease. Med Sci Monit 2011; 17: CR227–CR234.

    Article  CAS  Google Scholar 

  13. Liu X, Yang P, Wang C, Li F, Kijlstra A . IFN-alpha blocks IL-17 production by peripheral blood mononuclear cells in Behcet's disease. Rheumatology (Oxford) 2011; 50: 293–298.

    Article  CAS  Google Scholar 

  14. Sugita S, Kawazoe Y, Imai A, Yamada Y, Horie S, Mochizuki M et al. Inhibition of Th17 differentiation by anti-TNF-alpha therapy in uveitis patients with Behcet's disease. Arthritis Res Ther 2012; 14: R99.

    Article  CAS  Google Scholar 

  15. Murray PJ . The JAK-STAT signaling pathway: input and output integration. J Immunol 2007; 178: 2623–2629.

    Article  CAS  Google Scholar 

  16. O'Shea JJ, Holland SM, Staudt LM . JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368: 161–170.

    Article  CAS  Google Scholar 

  17. Coskun M, Salem M, Pedersen J, Nielsen OH . Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res 2013; 76: 1–8.

    Article  CAS  Google Scholar 

  18. Xavier JM, Krug T, Davatchi F, Shahram F, Fonseca BV, Jesus G et al. Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behcet's disease susceptibility. J Mol Med (Berl) 2013; 91: 1013–1023.

    Article  CAS  Google Scholar 

  19. O'Shea JJ, Plenge R . JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012; 36: 542–550.

    Article  CAS  Google Scholar 

  20. Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 2010; 32: 605–615.

    Article  CAS  Google Scholar 

  21. Kim J, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L et al. Imbalance of Th17 to Th1 cells in Behcet's disease. Clin Exp Rheumatol 2010; 28 (4 Suppl 60): S16–S19.

    PubMed  Google Scholar 

  22. Shimizu J, Takai K, Fujiwara N, Arimitsu N, Ueda Y, Wakisaka S et al. Excessive CD4+ T cells co-expressing interleukin-17 and interferon-gamma in patients with Behcet's disease. Clin Exp Immunol 2012; 168: 68–74.

    Article  CAS  Google Scholar 

  23. Na SY, Park MJ, Park S, Lee ES . Up-regulation of Th17 and related cytokines in Behcet's disease corresponding to disease activity. Clin Exp Rheumatol 2013; 31 (3 Suppl 77): 32–40.

    PubMed  Google Scholar 

  24. Akman-Demir G, Tüzün E, Içöz S, Yeşilot N, Yentür SP, Kürtüncü M et al. Interleukin-6 in neuro-Behcet's disease: association with disease subsets and long-term outcome. Cytokine 2008; 44: 373–376.

    Article  CAS  Google Scholar 

  25. Qi J, Tüzün E, Içöz S, Yeşilot N, Yentür SP, Kürtüncü M et al. Increased Notch pathway activation in Behcet's disease. Rheumatology (Oxford) 2014; 44: 373–376.

    Google Scholar 

  26. Yang J, Stark GR . Roles of unphosphorylated STATs in signaling. Cell Res 2008; 18: 443–451.

    Article  CAS  Google Scholar 

  27. Yang J, Liao X, Agarwal MK, Barnes L, Auron PE, Stark GR et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev 2007; 21: 1396–1408.

    Article  CAS  Google Scholar 

  28. Timofeeva OA, Chasovskikh S, Lonskaya I, Tarasova NI, Khavrutskii L, Tarasov SG et al. Mechanisms of unphosphorylated STAT3 transcription factor binding to DNA. J Biol Chem 2012; 287: 14192–14200.

    Article  CAS  Google Scholar 

  29. Hou S, Qi J, Zhang Q, Liao D, Li Q, Hu K et al. Genetic variants in the JAK1 gene confer higher risk of Behcet's disease with ocular involvement in Han Chinese. Hum Genet 2013; 132: 1049–1058.

    Article  CAS  Google Scholar 

  30. Hu K, Hou S, Jiang Z, Kijlstra A, Yang P . JAK2 and STAT3 polymorphisms in a Han Chinese population with Behcet's disease. Invest Ophthalmol Vis Sci 2012; 53: 538–541.

    Article  CAS  Google Scholar 

  31. Cenit MC, Ortego-Centeno N, Raya E, Callejas JL, García-Hernandez FJ, Castillo-Palma MJ, Fernandez-Sueiro JL et al. Influence of the STAT3 genetic variants in the susceptibility to psoriatic arthritis and Behcet's disease. Hum Immunol 2013; 74: 230–233.

    Article  CAS  Google Scholar 

  32. Oh HM, Ortego-Centeno N, Raya E, Callejas JL, García-Hernandez FJ, Castillo-Palma MJ et al. Autoreactive memory CD4+ T lymphocytes that mediate chronic uveitis reside in the bone marrow through STAT3-dependent mechanisms. J Immunol 2011; 187: 3338–3346.

    Article  CAS  Google Scholar 

  33. Kovacic JC, Gupta R, Lee AC, Ma M, Fang F, Tolbert CN et al. Stat3-dependent acute Rantes production in vascular smooth muscle cells modulates inflammation following arterial injury in mice. J Clin Invest 2010; 120: 303–314.

    Article  CAS  Google Scholar 

  34. Yeilding N, Szapary P, Brodmerkel C, Benson J, Plotnick M, Zhou H et al. Development of the IL-12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives—an update. Ann N Y Acad Sci 2012; 1263: 1–12.

    Article  Google Scholar 

  35. Criteria for diagnosis of Behçet's disease. International Study Group for Behçet's Disease. Lancet 1990; 335: 1078–1080.

  36. R Development Core Team. R: a language and environment for statistical computing 2013 R Foundation for Statistical Computing: Vienna, Austria.

  37. Tusher VG, Tibshirani R, Chu G . Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98: 5116–5121.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study is supported through grants of Turkish Scientific and Technical Council (TUBITAK, No: 106S320) and Marmara University (BAPKO, SAG-BGS-290107-0022 and SAG-A-090512-0132). JDW and MGD were supported by NIH 5P20GM103636-02.

Author information

Authors and Affiliations

  1. Division of Immunology, Department of Internal Medicine, Marmara University, School of Medicine Hospital, Istanbul, Turkey,

    A Tulunay, F Ture-Ozdemir & E Eksioglu-Demiralp

  2. Oklahoma Medical Research Foundation and Department of Biochemistry and Molecular Biology, Arthritis and Clinical Immunology Research Program, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    M G Dozmorov & J D Wren

  3. Department of Biostatistics, Bioinformatic Section, Translational Research Informatics Core (TRI Core), Virginia Commonwealth University, Richmond, VA, USA

    M G Dozmorov

  4. Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey,

    V Yilmaz & G Saruhan-Direskeneli

  5. Division of Rheumatology, Department of Internal Medicine, Marmara University, School of Medicine Hospital, Istanbul, Turkey,

    F Alibaz-Oner, G Ozen & H Direskeneli

  6. Division of Rheumatology, Department of Internal Medicine, University of Michigan, MI, Ann Arbor, USA

    A H Sawalha

Authors
  1. A Tulunay
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M G Dozmorov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Ture-Ozdemir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Yilmaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Eksioglu-Demiralp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F Alibaz-Oner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Ozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J D Wren
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G Saruhan-Direskeneli
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A H Sawalha
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Direskeneli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H Direskeneli.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on Genes and Immunity website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tulunay, A., Dozmorov, M., Ture-Ozdemir, F. et al. Activation of the JAK/STAT pathway in Behcet’s disease. Genes Immun 16, 170–175 (2015). https://doi.org/10.1038/gene.2014.64

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gene.2014.64

This article is cited by

Search

Advanced search

Quick links